1. Field of the Invention
The present invention relates to oral peptide pharmaceutical compositions having analgesic and/or cardiovascular activity, and to methods of enhancing bioavailability of such peptides when administered orally.
2. Description of the Related Art
Opiates such as morphine and codeine, or opiate-like synthetic drugs are currently used for the management of moderate to severe pain. Many endogenous peptides of mammalian and amphibian origin (e.g., the endorphins) also bind to opioid receptors and elicit an analgesic response similar to classic narcotic opiates. This led to the hope that these peptides might be produced commercially and administered to patients to, e.g., relieve pain. It was found, however, that side effects such as depression of cardiac and respiratory function, tolerance, physical dependence capacity and precipitated withdrawal syndrome are caused by nonspecific interactions between such peptides and central nervous system receptors. Such side effects are due to the interaction of these peptides with multiple opioid receptors. For this reason, peptides with a variety of structural modifications have been developed in an effort to develop peptide-based pharmaceuticals that are specific for a particular opioid receptor sub-type [mu, delta and kappa], and which produce long-lasting antinociceptive effects while minimizing undesirable side effects such as depression of cardiac and/or respiratory function, extended sedative activity, etc.
Peptide pharmaceuticals known in the prior art, including the analgesic peptides described above, frequently have been administered by injection or by nasal administration. A more preferred oral administration tends to be problematic because peptide-active compounds are very susceptible to degradation in the stomach and intestines and show poor bioavailability. For example, the prior art is not believed to have reported to achieve reproducible blood levels of opioid peptides when administered orally. This is believed to be because peptides lack sufficient stability in the gastrointestinal tract, and tend to be poorly transported through intestinal walls into the blood. However, injection and nasal administration are significantly less convenient, and involve more patient discomfort, than oral administration. Often this inconvenience or discomfort results in substantial patient noncompliance with a treatment regimen. Thus there is a need in the art for a more effective and reproducible oral administration of peptide pharmaceuticals including, but not limited to, peptide pharmaceuticals having analgesic and/or cardiovascular activity.
Proteolytic enzymes of both the stomach and intestines may degrade peptides, rendering them inactive before they can be absorbed into the bloodstream. Any amount of peptide that survives proteolytic degradation by proteases of the stomach (typically having acidic pH optima) is later confronted with proteases of the small intestine and enzymes secreted by the pancreas (typically having neutral to basic pH optima). Specific difficulties arising from the oral administration of a peptide involve the relatively large size of the molecule, and the charge distribution it carries. This may make it more difficult for such peptides to penetrate the mucus along intestinal walls or to cross the intestinal brush border membrane into the blood. These additional problems may further contribute to limited bioavailability.